FI116939B - Process for the preparation of novel, therapeutically useful heteroarylamine compounds - Google Patents

Description

A process for preparing sexually novel therapeutically useful arylamino compounds

BACKGROUND OF THE INVENTION The present invention hereinafter relates to the pharmaceutically acceptable salts of the heteroarylamines of formula I and such compounds. The compounds of formula I are acetyl-sterase inhibitors and are useful in the memory of patients suffering from Alzheimer's disease.

Alzheimer's disease is associated with degeneration of the forebrain cholinergic neurons, a fundamental component of cognitive fun> 15 memory. Becker et al., Drug Develop search, 12, 163-195 (1988). As a result of this generation, patients suffer from the disease, with a marked reduction in acetylcholine synthase choline acetyltransferase activity, acetylcholinesterase activity and choline coupling It is known that acetylcholinesterase: V; Bitters are effective for improving cholinergic function and are useful for improving memory in patients with Als:; By inhibiting 25 lycolin esterase enzymes, these compounds increase the amount of acetylcholine in the brain, which enhances memory. Becker et al., Cited above, complain that cholinesterase inhibition £ behavioral changes co-occur with predicted peak values of acetylcholine in aivc. .

2 11 also apply to acetylcholine esterase inhibitors of het amine.

The present invention relates to the preparation of novel heteroarylamine compounds of formula 5 and the pharmaceutically acceptable salts thereof.

Re N? 3 15 "---—-———

"M

wherein, instead of bonding to ring A, the group-containing side chain may alternatively be located on the carbon atom designated by an asterisk in ring 20 and R 3 may be optionally bonded re · · B; R 1 is phenyl, phenyl (C 1-6 alkyl, cinnamyl), heteroarylmethyl wherein the heteroaryl moiety of said heteroaryl is selected from the group consisting of Solo, thiazolo, thieno, pyrido and isoxazolo, and ψ said phenyl and said heteroaryl moiety may be substituted with one or two substituents independently selected from x including (C 1 -C 6) alkyl, (C 1 -C 4) alkoxy and halo R 2 and R 3 are independently selected se 3 R 4 and R 5 are independently selected from hydrogen and (C 1-6) alkyl; X is nitrogen or CH; Y is oxygen, sulfur or NR 6; R 5 is hydrogen, alkyl, CO (C); (4) alkyl-ta: -anyl, wherein the phenyl portion of said SO 2 -phenyl may be optionally substituted with 1 to 5 substituents independently selected from (C 1 -C 4) alkyl; n is an integer from 1 to 4; each q is independently 1 or 2; or sulfur, provided that each CHq group, already 1, must be a bond n and only one CH9 group, where q is 1.

Examples of pharmaceutically acceptable addition salts include hydrochloric acid, p-toluene acid, fumaric acid, maleic acid, citric acid, tartaric acid, salicylic acid, oxalic acid, hydrobromic acid, methanesulfonic acid, tartaric acid, diphenic acid.

As used herein, the term "halogen 11" refers to bromine or fluorine.

*: **: Preferred Compounds of Formula I are: -: - - - - - - - - - - - - -; , ^ / - 0 / ~ Rl. . ·. or 30 ♦ ·.

* X where X is CH, CCH 3, CCH 2 CH 3 or N; Y is NH, NCH3, S, O or NSQ2C6H5; R 2 and R 3 are independently selected from the group consisting of (C 1-4) alkyl, chloro, fluoro, amino, and -O-NHCCH 3; and R 1 is benzyl, methoxybenzyl, a fluorobenz group of the formula 10 or C 1 -C 3 -C 20 where W is hydrogen, (C 1 -C 6 alkyl, phenyl or benzyl) Particularly preferred are the compounds of formula I: ·· * 1- (2-methyl-1H-benzimidazol-5-yl) -3- [1,2-methyl) -4-piperidinyl] -1-propanone; * * * * * 1- (2-phenyl-1 H -benzimidazol-5-yl) -3- [1 (99 N -methyl) -4-piperidinyl] -1-propanone; 1- (1-Ethyl-2-methyl-1H-benzimidazol-5-y [1- (phenylmethyl) -4-piperidinyl] -1-propanone;: ***: 1- (2-Methyl-6) benzothiazolyl) -3- [1- (phenyl-1- (6-methylbenzo [b] thien-2-yl) -3- [1- (phenyl) -4-piperidinyl] -1-propanone; (3,5-Dimethyl-benzo [b] thien-2-yl) -3- [1-methyl-4-piperidinyl] -1-propanone; 5 1- (Benzo [b] thien-2-yl) -3 - [1- (phenylmethylpiperidinyl] -1-propanone; 1- {benzofuran-2-yl) -3- [1- {phenylmethylpiperidinyl] -1-propanone; 1- (1-phenylsulfonyl-6-) methyl indol-2-yl [1- (phenylmethyl) -2-piperidinyl] -1-propanone; 1- (6-methylindol-2-yl) -3- [1- (phenylmethylpiperidinyl) -1- propanone; 1- (1-phenylsulfonyl-5-aminoindol-2-yl (phenylmethyl) -4-piperidinyl] -1-propanone; 15 1- (5-aminoindol-2-yl) -3- [1 - (phenylmethyl piperidinyl] -1-propanone; and 1- (5-acetylaminoindol-2-yl) -3- [1- (phenylmethyl) -4-piperidinyl] -1-propanone.

Examples of other compounds of Formula I include: 1- (6-quinolyl) -3- [1- (phenylmethyl) -4-piperidinyl] -1-propanone; 1- (5-indolyl) -3- [1- (phenylmethyl) -4-piperazinyl] -1-propanone; · · · · · ··· 25 1- (5-benzstienyl) -3- [1- (phenylmethyl) -4:. dinyy1i] -1-propanone; 1- (6-quinazolyl) -3- [1- (phenylmethyl) -4- [4] · dinyl] -1-propanone; . 1- (6-Benzoxazolyl) -3- [1- (phenylmethyl) piperidinyl] -1-propanone; * 1 · 1 cis ___________ 1- (5-Chloro-benzo [b] ] thien-2-yl) -3- [1- (phenylmethyl) -4-piperidinyl] -1-propanone; 1- (5-azaindol-2-yl) -3- [1- (phenylmethyl peridinyl) -1 1- (6-azabenzo [b] thien-2-yl) -3- [1- (phenyl) -4-piperidinyl] -1-propanone; 1- (1H-2-oxo-pyrrolo [? 2 ', 3 1,5,6] benzo [b] thiyl) -3- [1- (phenylmethyl) -4-piperidinyl] -1-prop 1- (6-methyl-benzothiazol-2-yl) -3 - [1- (phenyl) -4-piperidinyl] -1-propanone; 1- (6-methoxyindol-2-yl) -3- [1- (phenylmethylpiperidinyl) -1-propanone; 6-methoxy-benzo [b] thien-2-yl) -3- [1- (phenyl) -4-piperidinyl] -1-propanone; 1- (6-acetylamino-benzo [b] thien-2-yl) yl) -3-ylmethyl) -4-piperidinyl] -1-propanone; and 1- (5-acetylamino-benzo [b] thien-2-yl) -3-ylmethyl) -4-piperidinyl] -1-propanone.

The compounds of Formula I may have 20 centers and may therefore exist in different isomeric forms.

9 9

The group of compounds of formula I comprises all isomers of the compounds of formula I, including mixtures thereof.

Detailed Description of the Invention

Compounds of formula I may be prepared that: · · *

a) a compound of formula IA

30 * '* · / m * / 7 11

where side chain / OH instead of ring A bonding

-CH-, may alternatively be bonded to carbon 5, indicated by an asterisk in ring B, and R 2 and I may be optionally bonded to ring B, and R 1, R 2, R 3, x, y, q and n are defined above, ε and reacting the compound thus formed with i 10 capable of forming a compound having IB

—Rl where R 1 ^ R 27 ~ R 57 ~ ^ T ~ 1 ^ ® ^^ ar-rr ^ or ^ as defined above

b) a compound of formula I-B

p 3- 20 v M / n yT * / * '_ /

:. ·. 1% I ”B

• · i U ¥ tm! Where n is 2, 3 or 4 and the (CH) group always contains] <* * n carbon-carbon double bond and R 1, R 2, R 3, x, y, c * * * are as defined above re. with hydrogen in the presence of a catalyst; it • * φ

* · [· * 30 c) a compound of formula I-C

8 where R 1 and R 2 are as defined above, is contacted with a compound of the formula R 6 L wherein L is defined above and L is a leaving group; or

d) a compound of formula XV

5 R2 · 7 «· / \

CCHq) n - / NH

° '_ /

R3_XV

wherein R 1, R 2, R 3, x, y, z, q and m are as defined above reacted with a compound having ke 15 wherein L is a leaving group in the presence of a base.

The preparation of compounds of formula I is illustrated in the following reaction schemes. Unless otherwise stated, the reaction schemes and subsequent embodiments include R 1, R 2, R 3, R 4, R 5, R 6, n, q, p, X, Y and Structural Formula I as defined above.

The symbol * (that is, a star) appearing in the use · · 5.5,5 reaction diagrams means, for each r where it occurs, the side chain already: ozs • · · "I» n "C, -C, or The -C group may bind to ring A. 25 alternatively be bound to a carbon atom · ;;; is marked with an asterisk in ring B. In the reaction scheme * * * * · * * fused benzo group.

* • · · # i · · 1 * • · • * 11 9

R2 / ΓγΧΛ II / \ («J | B y + HC- <CHq) n— 10 p

II III

R2

Vc- <CHq) n— / \ l — R1, 0 Vpk 'w rv • · • I «•« «« · ··· - · • • • • • • * R2 * «· R \ t. Ö ^ ~ o ~ 1:

R 2 O 5 / rv ^ -CH 3 o "+ H-C- (CHq) n-g- ^ R 3

V VI

10

Rf _ 0 OH j- \ X ^ \ r ^ \ c - 'C-CH? -CH- (CHp) n.g (N-R1 15 f' _ /

r3 VII

20

R f O / -V

• V. -S. v n / \ t V · 1 2 r \ CH = CH- <CHq> n_2-1 N-R1 •: ***: {fi 1 \ _ /

Ui 25 Υ _ ^^ γ /

.: · I-B

• aa »» aa • a a a a a a 30 «· · · 1 ·.

* · 1 Re Λ «· k n. -......

· \ Y. / \ 2 ··· '11

Scheme 3 = J ^ O · 8 ^ · * - • “• -« - O ··

B

IX X

B

XI

15

XII

* · * * «• * • · * · *

:. :: 25 N

: 7, ^ r ^ _ <CH,> v Vri · ** · u <«« «· • · ·

L-C

30 ft ft · "· * • ft * • ft • *

Scheme 4 12 5 R \ 0 / - \ X (CHq) ^ - / N Rl (fl-T — By * \ _ / 1 ° r3

I-E

+

PeS5 15 it

20 S

XIII

• · 9 * · t «· • # * *« 9

* · 9 Ä V

• · · 55 * ·: ··: r2 c _ ·: V ~ x X 'ΛΑ i {flTvf \ ^ ::': 30

··· n J

J

Scheme 5 13 y \ C- <CH „) \ —l

5 C FliC / '- U

R3 1-6 10

R \ z / - \ 0 V

V CCHp) n - / N - c - 0 - C H - i (° ^ L / * ^ _ / 15

r3 XIV

20 :: ': 25 r3 xv * * ·

IM

* «· · · ··« ^ • · · ♦ · *. . ·. 30 p2, _ R z · / -y 14

Scheme 1 illustrates a method of combining formula I wherein Z is oxygen and sd containing a group Z

IV

5 -C-, is bonded to the carbon atom designated in Ring B (which are referred to hereinafter as I-A compounds).

Starting materials of formulas 11 and 111 are commercially available or can be prepared by the synthetic methods set forth in Letter 10. (See J. Med. 33, 2777 (1990)? Tetrahedron Letters, 30, 6117 (Eur. J. Med. Chem., 25, 191 (1990); Heterocycles, 1989); J. Org. Chem., 47). , 757 (1982); J. Org. Cl. 4350 (1989); Tetrahedron, 44, 3195 (1988); Zur. 15 Chem. & Chim. Ther., 21, 223 (1986); Chem. Ber (1954); Tetrahedron, 28, 2553 (1972); J. Chem. S 1733 (1968); U.S. Patent 4,902,694; J. Heterocycld. 25, 1271 (1988); Bull. Cem. Soc. Jpn., 58, 785 (1988). Chem. Soc., 12, 561 (1975) and Synthetic Cc 20, 14, 947 (1984).

Referring to Scheme 1, a compound of formula II is reacted with a suitable compound of formula III in the presence of a base of formula IV. . to form a compound. This reaction is carried out * •. .

; Suitable solvents which are inert to the reaction at a temperature of about -78 ° C to room temperature, preferably from about -78 ° C to about 0 ° C *, are tetrahydrofuran (THFI, ethylene, methylene chloride, benzene and dioxane: the bases are lithium bis (trimethylsilyl) amide,]; ***: isopropylamide, sodium diisopropylamide, by reaction with an appropriate substance. manganese dioxide, chromium and selenium dioxide The manganese dioxide would preferably be carried out at a reaction temperature inert to about 80 ° C, preferably about 80 ° C. Examples of suitable solvents are olefin chloride, chloroform, ethyl acetate, B The solvent is preferably methylene glass benzene.

Scheme 2 illustrates a process for the preparation of compounds of the formula wherein Z is oxygen and n is 2 (hereinafter referred to as: compounds of formula IA ') and compounds of formula I wherein n is 2, 3 or 4 and (CHq) n group contains * one carbon-carbon double bond (hereinafter referred to as the formula IB). Referring to Scheme 2, starting materials of i20 V and VI may be commercially available or may be obtained as disclosed in the literature. (, V. Org. Chem., 54, 4350 (1989); Tetrahedron 44, 3191-9.

Chem. Pharm. Bull., 39, 181 (1991); Chem. Ber., 1986: V; and J. Ind. Chem. Soc. 12, 561 (1975).

| As shown in Scheme 2, a compound of formula VI is reacted with i * * * ·. · 'Of formula VI in the presence of a base to form a compound of formula VII i * * * V *. Suitable bases for this are sodium hydride, lithium bis (trimethyl amide, piperidine, pyrrolidine, lithium diisopropyl, sodium diisopropylamide, n-butyllithium

The reaction temperature may be from about -78 ° C to about 0 ° C, and preferably from about -78 ° C to about 0 ° C.

If the reaction of the compounds of formulas V and VI is carried out with sodium or potassium (C 4) a), it is preferable to use te DMF, THF or methylene chloride as the solvent, using mu! without using (C 1 -C 4) alcohol, and carrying out the reaction at about -40 ° C to about 80 ° C, about 0 ° C to about room temperature.

for this compound, the corresponding compound is obtained. Alternatively, the elimination is accomplished by contacting a compound of Formula VII, rc, in the presence of a base with a reagent capable of forming a leaving group in its reaction with a roxy group of the formula. Suitable reagents include ethyl anhydride, R 7 SO 2 Cl, R 7 COO 1, R 70 COO and R 7 NHCO selected from; (C 1-4) alkyl or phenyl Mahe substituent tin (C 1-6) alkyl, (C 1-4) alkoxy or nil 20, examples of suitable bases include triethylamine, propylethylamine, diazabicycloundecane (DBl-V. Azabicycloneonone). The solvent may be any inert solvent (e.g. methylene chloride, klc * · THF or toluene) The reaction temperature may be from about 0 ° C to about 60 ° C, and is preferably from about 0 ° C to about room temperature.

f * * ··· * Compounds of formula I-B may be

*. *: by preparing the appropriate formula VII

The compound to react the Burgess1 Inner Salt The Burgess Inner Salt may be prepared from clocyl isocyanate, methanol and triethyl 17 at a temperature of about room temperature to about solvent reflux temperature, preferably about 50 ° C to about 80 ° C.

The corresponding compound of formula 1-A 'is then cast by hydrogenation of the compound of formula I-B in the preceding step. The hydrogenation is carried out using platinum dioxide or palladium at a pressure of about 2.1 kg / cm 2 (30 psi to 3.5 kg / cm 2 (50 psi)). Suitable reaction inert solvents are THF, methanol, ethanol, ethyl acetate mixtures. The solvent is preferably ethanol and TI or a mixture of ethanol and ethyl acetate The reaction temperature is between about 0 ° C and about 60 ° C. Preferred J is about room temperature.

15 Preparation of Compounds of Formula

ID, is depicted in Scheme 3. Compounds of formula I1 are those compounds of formula I wherein ren Benzo, Y is NR6, R6 is hydrogen, X is nitrogen, R3 is vi bonded to the carbon atom represented by the delta (*). ring B. The compounds of formula ID were joined by those compounds of formula 1 wherein ring A o. Y is NR 6, R 6 is other than hydrogen, X is nitrogen, R

and R 2 is bonded to the carbon atom of • *. . with an asterisk (*) on ring B.

Referring to Scheme 3, the reaction of Formula IX with an aldehyde of Formula X to prepare a compound of Formula ··· is carried out according to Scheme 2 and illustrated in Reaction Steps V - * VII -> IB - * IA *.

* · / · / * 30 Compound of formula XII obtained cyclisod: ***; in the presence of an acid, λ 18 of formula I-C is about room temperature and about 120 eC. Temperatures between 60 ° C and about 90 ° C are preferred.

The R6 group can be added to Formula I-C to give the corresponding compound of Formula I-D by coupling a suitable Formula I-C with a compound of Formula R6L, and a leaving group. This reaction is carried out in a typical inert solvent in the presence of a base in the range of about -78 ° C to about solvent distillation temperature. Suitable bases include potassium hydride, lithium diisopropylamide, t-butyl potassium t-butoxide. Suitable solvents are THF, nichloride, benzene, ether, toluene or d. The reaction is preferably carried out in THF in the presence of sodium at a temperature of about 0 ° C to about 30 ° C.

Scheme 4 illustrates a compound of formula I: wherein Z is sulfur (which compounds, hereinafter referred to as XF, combines compounds of 1-E. This conversion is carried out as follows: V) a compound of formula IE to react with Lawesson , 4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphate: · · · β · β 2,4-disulfide) or phosphorus pentasulfide (P2S5) * * · 25 This reaction is typically carried out in a in a solvent such as THF, the acetones: in chloroform or toluene at a temperature of about 110 ° C to about 110 ° C are preferably carried out in THF or toluene at about 60 ° C. at a temperature of about 80 ° C.

···: Compounds of Formula I (wherein R 19 are compounds) as described below in Section 5.

First, the formula I-6 is combined with a chloroformate of the formula 5 O

C 1 -C 9 R 9 where R 9 is -C 1 CHCH 3, -CH 2 CH 3 or -CH 2 C 6 H 5. The preferred reactant is 1-chloroethyl chlorophenol This reaction which gives a compound of formula XIV is generally carried out for the reaction inc 10 in a solvent such as methylene chloride, chlorodichloroethane, THF or toluene, edi toluene, at a temperature in the range of about 100 ° C. preferably between about 80 ° C and about 10 ° C. The heating of the thus formed compound of formula XIV with (C1,4) alcohol, preferably methanol in ethanol, affords the corresponding compound of formula XV. The reaction temperature may be between about 80 ° C and reflux approximately solvent recovery dist.

The compound of formula 2 · 1 · · · formed in the preceding step is then alkylated and converted to the corresponding compound of formula I by reaction with a compound of formula R 1L, · · · 25 is a leaving group, in the presence of a base. An example of leaving groups is chloro, bromo, jocalate, tosylate and triflate (OTf). Suitable t · 1 * · 1 are pyridine, triethylamine, dimethylamino and potassium carbonate. Triethylamine is preferably carried out in a reaction inert reaction. such as methylene chloride or DMF, age 20 are suitable, and ambient pressure (generally about 1 l is preferred for its practicality. Also, in the case of reactions in which the preferred patient varies with the particular compounds in question, the preferred temperature is not indicated. For such reactions, the thermal reactants can be determined by observation using thin layer chromatography.

The compounds of Formula 5 may be administered by a variety of methods, for example, by oral administration in the form of tablets or tablets, parenterally in the form of a sterile suspension or suspension, and, in some cases, in the form of a solution. The free base forms can be prepared and administered in the form of their pharmaceutically acceptable acid addition salts.

The daily average of the compounds of Formula I is generally in the range of about 1 to about 300 mg / day for an adult human and may be administered in single or divided doses.

If the compounds of the formula I are included in a solution for phthalogenetic solution for parenteral administration, the compounds will be present at a concentration of * 5 * 2 to at most 1% by weight, and preferably in the range of from 1 to 10%; 70% by weight (based on total unit weight).

····· 25 oral dosage units typically contain n ·: · 100 mg of active compound (s).

····

The compounds of the formula I may be administered * · * * in an inert diluent or as an edible carrier. or may be included in a gelatin capsule

HI * 30 or they can be compressed into tablets. For such • •

Λώη Ί ei eol f äa iraVi inl-äan Π ^ ^ alri-i ΐττ ·! n4-fa * rU

21

The activity of the compounds of the formula I as lycolinesterase inhibitors can be determined by standard biological or pharmacological experiments. Such a method for inhibiting cholinesterase inhibition is described by Ellman et al. and Rapid Colorimetric Determination of Acetylchase Activity, "Biochem. Pharm. 1, 88, (1961).

The present invention is illustrated by the following symbols. It is understood, however, that the invention was not resolved to the specified details of these examples, the lamina points being uncorrected. The proton nuclear magnetic resonance spectrum (¾ NMR) and the C13 nuclear magnetic resonance spectrum (C13 NMR) were measured for solutions in deuterok (CDCl3) and peak positions are reported in mils 15 (ppm) calculated from tetramethylsilane

The forms of the peaks are expressed by the following s, singlet; d, doublet; t, triplet; q, kv m, multiplet; b, wide.

Example 1 1- [2- (5-Methyl-benzothienyl)] -3- [1- (phenyl) -4-piperidinyl] -2-propen-1-ol e. methyl benzo "** (356 mg, 2.4 mmol) in 10 mL dry tetrahydro" (THF) was treated with n-butyllithium (n-Buli) at 25 -10 ° C and stirred at room temperature. ··. 30 minutes. A solution of 3- [4- (N-benzyl ···· dinyl)] propenal (550 mg, 2.4 mmol) in 5 mL of sc · · · * tetrahydrofuran (THF) was added to the reaction mixture at.. the reaction of mixing 30 was quenched with water and the mixture was extracted with k * · * · *.

22

The organic layer was dried and evaporated to give 750 mg (90%) of the desired product.

1 H NMR (CDCl 3) δ 1.3-2.1 (m, 7H), 2.3-2.5 (m, 3.0 (m, 2H), 3.47 (s, 2H), 5.37 ( d, 1H), 5.6-5.2H), 7.0-7.7 (m, 9H) ppm.

The title compounds of Examples 2-4 were prepared by a method similar to that described in Example 1 Example 2 1- [2- (6-Methyl-benzothienyl)] - 3- [1- (phenyl) -4-piperidinyl] -2-propene. 1-ol 1 H NMR (CDCl 3) δ 1.3 - 2.0 (m, 7H), 2.4 (s, 3H), 2t (m, 2H), 3.45 (s, 2H), 5.35 (d, 1H), 5.6-5.8 7.0-7.6 (m, 9H) ppm.

Example 3 1- [2- (2,5-Dimethyl-benzothiothienyl)] - 3- [1-methyl) -4-piperidinyl] -2-propen-1-ol 1 H NMR (CDCl 3) δ 1.35 - 2.0 (m, 7H), 2.3 (s, 3H), 3H), 2.8 - 2.9 (m, 2H), 3.5 (s, 2H), 3.7 - 3, 5.5-5.9 (m, 3H), 7.0-7.8 (m, 8H) ppm. Example 4 1- (2-Benzothienyl) -3- [1- (phenylmethyl) ridinyl] -2-propen-1-ol * · 1 H NMR (CDCl 3) δ 1.3 - 2.0 (m, 7H) , 2.7-2.9 (m, 1 (s, 2H), 5.4 (d, 1H), 5.6-5.8 (m, 2H), 7.1 (s,] ♦ ·: 7.3 (m, 7H), 7.65 (dd, 1H), 7.72 (dd, 1H) ppm: Example 5 ss * *, 5-methylbenzothien-2-yl-2- [1- (Phenyl in V: 4-piperidinyl) vinyl ketone

A solution of 1- [2- (5-methyl-benzothienyl)] -3- [1- (phenylmethyl-piperidinyl) -2-propen-1-ol (750 mg, 21 (• s · 23

The filtrate was evaporated to dryness to give 602 mg of crude brown semi-solid. 1 H NMR (CDCl 3) δ 1.4-1.9 (n, 4H), 2.0 (dt, 2H)

2.3 (m, 1H), 2.4 (s, 3H), 2.9-3.0 (m, 2H), 3.5 δ 6.8 (δ, 0.4H), 6.85 ( s, 0.6H), 7.0 - 7.18 (m, U)

7.9 (m, 9H) ppm.

The title compounds of Examples 6 and 7 were prepared by a method similar to that described in Example 5 Example 6 2,5-Dimethylbenzothien-2-yl-2- [1- (methyl) -4-piperidinyl] vinyl ketone NMR (CDCl3) , Δ-2.0 (m, 4H), 2.1 (dt, 2H),: (m, 1H), 2.56 (s, 3H), 2.8 (s, 3H), 2.9 - 3.05 3.56 (s, 2H), 6.72 (s, 0.4H), 6.8 (s, 0.6H), δ 0.6H), 7.1 (d, 0.4H) , 7.3 - 7.8 (m, 8H) million

Example 7

Benzothien-2-yl-2- [1- (phenylmethyl) -4-] yl] vinyl ketone 1 H NMR (CDCl 3) δ 1.4-1.9 (m, 4H), 1.95-2.1 (20 , 2 - 2.35 (m, 1H), 2.8 - 3.0 (m, 2H), 3.54 (s, 2 (s, 0.4H), 6.9 (s, 0.6H) , 7.1 (d, 0.6H), 7.15 (δ 7.2 - 8.0 (m, 10H) ppm.

Example 8 1- (5-Methyl-benzo [b] thien-2-yl) -3- [1- (*** * 25-methyl) -4-piperidinyl] -1-propanone

A solution of 5-methyl-benzothien-2-yl-2- [1- (phenyl: 4-piperidinyl)] vinyl ketone from Example 5 (600 mg, 1.6 mmc of ethanol (20 ml) and ethyl acetate (40 ml) were treated with platinum oxide (PtO 2) (60 mg and hydrogenated at 3.5 kg / cm 2 for 2 hours. (24 chromatographically, eluting with kCl and finally 2%). methanol chloroform solution, 232 mg of the title compound were obtained.

* 1 H NMR (CDCl 3) δ 1.2 - 2.1 (m, 9H), 2.52 δ 2.9-3.0 (m, 2H), 3.05 (t, 2H), 3.52 ( s, 2H), 7 (m, 6H), 7.7 (s, 1H), 7.75 (d, 1H), 7.9 (s, 1H) n.

The title compound of Examples 9-11 was synthesized by the method of Example 8 in Figure 10.

Example 9 1- (6-Methyl-benzo [b] thien-2-yl-3- [1- (Ferryl) -4-piperidinyl] -1-propanone 1 H NMR (CDCl 3) δ 1.2 - 2.05 (m, 9H), 2.5 δ 2.7 - 2.8 (m, 2H), 3.0 (t, 2H), 3.5 (s, 2H), 7.2 - 6H), 7, 65 (s, 1H), 7.8 (d, 1H), 7.9 (s, 1H) million

Example 10 1- (3,5-Diethyl-benzo [b] thien-2-yl) -3- [1- (methyl) -4-piperidinyl] -1-propanone 1 H NMR (CDCl 3) δ 2 - 2.0 (m, 9H), 2.5 2.75 (s, 3H), 2.8 - 3.0 (m, 4H), 3.5 (s, 2H), 7.2 -: A: 8h) ppm.

*: · '* Example 11 • 1- (Benzothien-2-yl) -3- [1- (phenylmethyl) -3,5-peridinyl] -1-propanone. 1 H NMR (CDCl 3) δ 1.1 - 2.0 (m, 9H), 2.8 - 2h>, 3.05 (t, 2h, 3.5 (s, 2h>, 7.2 - 7.5) (7h, 7H (m, 2H), 7.95 (s, 1H) ppm.

Example 12 * "·" 30 Benzofuran-2-yl-2- [1- (phenylmethyl) -4-f] · * · _.___ 1 J 1___5 —___ * 1 _i____.

Furan-2-ylmethylketone (0.48 g, 3 mmol) in 3 mL; THF, and the mixture was stirred at this temperature for hours. The reaction was quenched with water, saturated brine, and extracted with ethyl acetate. The organic layer was dried and evaporated to give 1.117 g of product as an oil. The oil was added to 15 mL of methylene chloride and the solution was treated with chloride (0.24 mL, 3 mmol) and triethylamine (13 mmol) at room temperature. The mixture was stirred at room temperature overnight, then quenched with water and extracted with methylene. The organic layer was dried and evaporated to give 0.827 g of crude material which was purified by pogel column chromatography using first chloroform and finally 5% methanol to form mg of grayish sp 186-188 ° C.

1 H NMR (CDCl 3) δ 1.8 - 3.0 (δ, 7H), 3.1 - 3.4 (m, (br s, 2H), 6.9 (s, 0.4H), δ, 96 (s, 0.6H), 7.1 (c 20 7.15 <d, 0.4H), 7.2-7.7 (m, 10H) ppm.

Example 13

Benzofuran-2-yl-3- [1- (phenylethyl) -4-] * * m'm ', yl] -1-propanone. . A solution of benzofuran-2-yl-2H-ylmethyl) -4-piperidinyl] vinyl ketone (4 in a mixture of ethanol (70 mL) and ethyl acetic acid (40 mL) was treated with platinum oxide (80 mg). ) with ···: The wheel at 3.15 kg / cm2 (45 psi) for one turn

The mixture was filtered through CeliteR and the filtrate was dried to give an off-white solid ···: *** which was recrystallized from ethyl acetate.

26

Example 14 1- [2- (N-Phenylsulfonyl-6-methylindo-1- [1- (phenylmethyl) -4-piperidinyl] -2-p was a solution containing N-phenylsulfonyl-6-indole (1, 18 g, 4.34 mmol) in 30 mL of dry THF was placed at -78 ° C and treated with 3.5 mL (5 mol of 1.5M lithium diisopropylamide; hexane solution at -78 ° C). After stirring at -78 ° C for 1 hour, a solution of 3- [1- (phenylmethylpiperidinyl) -2-propenal (1.0 g, 4.36 mmol) in dry solution was added at -78 ° C. THF, and the mixture was stirred at this temperature for 40 minutes, quenched with water, extracted with chloroform, the organic layer was evaporated to dryness to give 2.23 g of an orange oil, and the oil was purified by silica gel column chromatography using 2% methanol / 0 g of the title compound as a 20 oil.

1 H NMR (CDCl 3) δ 1.4 - 1.8 (m, 4H), 1.9 - 2.1 (m, · (s, 3H), 2.85 - 2.95 (m, 2H), 3.3 (br s, 1H), 3.5 5.6-5.9 (m, 3H), 6.55 (s, 1H), 7.02 (dd, 1H), δ (m, 12H) ppm.

* Example 15 N-phenylsulfonyl-6-methylindol-2-yl (phenylmethyl) -4-piperidinyl] vinylc * · * · · · · A solution of 1- [2- (N-phenylsulfcmethylindolyl) )] -3- [1- (phenylmethyl) -4-piperidine] -2-propen-1-ol (1.2 g, 2.4 mmol) in 30 mL ···; ***; methylene chloride, was treated with manganese dioxide by column chromatography on silica gel using chloroform first and finally methanol 2, chloroform solution, to give 740 mg (62% of the title compound as a yellow oil *

Δ NMR (CDCl 3) δ 1.4-1.8 (m, 4H), 1.9-2.1 (m, 2H

2.3 (m, 1H), 2.5 (s, 3H), 2.85-3.0 (m, 2H), 3.5 6.55 (s, 0.45H), 6.65 (s) , 0.55H), 6.9 (d, 0.55H), 0.45H), 7.0 (s, 1H), 7.1 (d, 1H), 7.25 - 7.55 7.9 8.1 (m, 3H) ppm.

Example 16 1- (1-Phenylsulfonyl-6-methylindol-2- [1- (phenylmethyl) -4-piperidinyl] -1-prt Solution containing N-phenylsulfonyl-1-indol-2-yl-2 - [1- (Phenylmethyl) -4-piperidinyl] ketone (360 mg, 7.2 mmol) in THF and ethanol (25 mL / 25 mL), treated with platinum oxide (PtO 2) and hydrogenated at 3.15 kg / cm 2: n (45 psi) pair minutes The mixture was filtered through Celite R. Dryed to give a dark oil, silica gel column chromatography eluted with chloroform as eluent to give 200 l of a co-compound as a yellow oil.

*** [*] NMR (CDCl 3) δ 1.2 - 1.75 (m, 7H), 1.8 - 2.0 (m, (s, 3H), 2.8 - 3.0 (m, 4H), 3.5 (s, 2H), 7.0 (s, δ · 25 (d, 1H), 7.2 - 8.0 (m, 12H) ppm.

Example 17 1- (6-Methyl-indol-2-yl) -3- [1- (phenylmethyl) -4,6-piperidinyl] -1-propanone

A suspension of N-phenylsulfonylmethylindol-2-yl-2- [1- (phenylmethyl) -4-pipe: ***; lijetyl ketone (150 mg) in 20 mL of methanol, hand MΛΛ 28 and evaporated to give 100 mg of the title compound as a brown solid.

NMR (CDCl 3) δ 1.2 - 1.8 (m, 7H), 1.8 - 2.0 (m,: (s, 3H), 2.8 - 3.0 (m, 4H), 3, Δ (s, 2H), 6.95 (d, 5 (s, 1H), 7.2-7.35 (m, 6H), 7.55 (d, 1H) million

Example 18 1- (2-Benzothiazolyl) -3- [1- (phenylmethylpiperidinyl) -2-propen-1-ol

A solution of benzothiazole (10 1.8 mmol) in 5 mL of dry THF was treated with a solution of 1.5-mc lithium diisopropylamide in cyclohexane at -78 ° C and stirred at this temperature for 1 minute. At -78 ° C, a solution of 3- [1- (phenylmethyl) -4-piperidinyl] pre-15 (452 mg, 1.97 mmol) in 3 mL of dry THF was added and the mixture was stirred at this temperature for 30 minutes. The reaction was quenched with water and the mixture was extracted with chloroform, which layer was dried and evaporated to give a thick yellow oil in quantitative yield.

1 H-NMR (CDCl 3) δ 1.6 - 2.15 (m, 7H), 2.85 - 3.0 3.5 (s, 2H), 5.5 (d, 1H), 5.7 - 6 , 1 (m, 2H), 7.2 (7H), 7.9 (d, 1H), 8.0 (d, 1H) ppm.

•. * / m \ Example 19 • *. 2-Benzothiazolyl-2- [1- (phenylmethyl) · [2 R] ridinyl] vinyl ketone

A solution of 1- (2-benzothiazole) was added

• [5- (1- (Phenylmethyl) -4-piperidinyl] -2-propane) (654 mg, 1.8 mmol) in 25 mL of methylene chloride was treated with MnO2 (0.782 g, 9 mmol). and heaters: 30 for redistillation. After 3 hours, the filtrate was filtered through Celite® and the filtrate evaporated m λ m 29 0.487 g of an amber oil which solidified over.

1 H NMR (CDCl 3) δ 1.5 - 1.9 (m, 4H), 2.0 - 2.15 2.32.5 (m, 1H), 3.5 (s, 2H), 7.2 - 7 , 6 (m, 9H), 5 H), 8.2 (dd, 1H) ppm.

Example 20 1- (Benzothiazol-2-yl) -3- [1- (phenylmethyl-piperidinyl) -1-propanone

A solution of 2-benzothiazol-10- (phenylmethyl) -4-piperidinyl] vinyl ketone (0.4 mmol) in a mixture of ethyl acetate and ethanol (10 mL) was treated with PtO 2 (20 mg) and pressure at 3.5 kg / cm 2 3 hours. The mixture was filtered through teR, and the filtrate was evaporated to dryness to give 0.154 g of a dark oil, the oil was purified by silica gel flash chromatography using 37 mg of the title compound as a brown NMR (CDCl 3) 1.2-1.4 (m, 3H), 1.7 - 1.85 1.85 - 2.1 (m, 2H), 2.8 - 3.0 (m, 2H), 3.3 (dd, 20 (s, 2H), 7.2 - 7.4 (m, 5H), 7.45-7.65 (m, 2 (dd, 1H), 8.2 (dd, 1H) ppm.

.V. EXAMPLE 21 N, N * phenylsulfonyl-5-nitroindole. A solution of 5-nitroindole (** · 25 10 mmol) in 30 mL of dimethylformamide (DMF) was treated with 60% sodium hydride (0.44 g, 11 mmol · · *). After 3 minutes nisulfonyl chloride (1.766 g, 10 mmol) was added and the mixture was stirred at room temperature overnight and treated with: 30 water which precipitated and filtered to give a yellow solid, already 30 * Η NMR (CDCl 3). Δ 6.82 (d, 1H), 7.45 - 7.55 (m, 2H) 1H), 7.72 (d, 1H), 7.9 (m, 2H), 8.1 <d, 1H ), 8.2 8.5 (d, 1H) ppm.

Example 22 5 N-Phenylsulfonyl-5-nitroindol-2-yl; nylmethyl) -4-piperidinyl] vinyl ketone A solution of N-phenylsulfonyl indole (646 mg, 2.14 mmol) in 10 mL of dry THF was treated with lithium diisopropylamide (1,5 mol; 10 in cyclohexane) (1, After 7 hours at -78 ° C, 7 mL, 2.6 mmol) at -78 ° C, added a solution of size containing 3- [4- (N-phenylmethyl] yl)] propenal (490 mg, 2.14 mmol) in 2 mL of THF at -78 ° C. After keeping the mixture at -78 ° C for 15 minutes, the reaction was quenched with water and extracted with methylene chloride. The organic layer was then evaporated to give 1.149 g of an oil. The oil was dissolved in 30 mL of benzene, treated with MnO 2 (1.86 g, 21.4 mmol) and heated at 20 ° C under distillation for 4 hours. Thereafter, an additional 900 mg of MnO 2 and the mixture was refluxed:? conditions overnight. The mixture was filtered The Celite R filtrate was evaporated to a brown oil which was pure; »· • β · Λ using silica gel column chromatography using • ♦ ft '* 25 tin chloroform to afford the title compound as an oil.

1 H NMR (CDCl 3) δ 1.45-1.95 (m, 4H), 1.95-2.1: 2.15-2.4 (m, 1H), 2.9-3 , 05 (m, 2H), 3.55 (s,

(s, 0.5H), 6.62 (s, 0.5H), 6.98 (d, 0.5H), 7.05 ψ 7.1 (s, 1H), 7.2 - 7.4 (m, 4H), 7.5 - 7.7 (m, 4H)

8.15 (m, 2H), 8.2-8.4 (m, 2H), 8.5 (d, 1H) m: 31

Example 23 N-phenylsulfonyl-5-nitro-indol-2-yl-2-methylmethyl) -4-piperidinyl] ethyl ketone

A solution of N-phenylsulfonyl-5-indol-2-yl-2- [1- (phenylmethyl) -4-piperidinyl] -ketone (187 mg # 0.35 mmol) in ethyl acetate and a mixture (20 mL / 8 mL) was treated With PtO 2 and hydrogenated at 2.8 kg / cm 2 (40 psi) at 1, E The mixture was filtered through CeliteB and the filtrate evaporated to give 177 mg (100%) of a brown oil.

1 H NMR (CDCl 3) δ 1.1 - 2.0 (m, 9H), 2.75 - 2.9 2.92 (t, 2H), 3.42 (s, 2H), 6.68 (d , 1H), 6.72 (6.8 (s, 1H), 7.1-7.5 (m, 8H), 7.7-7.9 (m, 3H).

Example 24 5-Nitroindol-2-yl-2- [1- (phenylmethyl) dinyl] ethyl ketone

A solution of N-phenylsulfonylindol-2-yl-2- [1- (phenylmethyl) -4-piperidinyl] ketone (160 mg, 0.32 mmol) in a mixture of <methanol and 2 mL of 2N NaOH, heated recovery .V. conditions for 2 hours. The mixture was evaporated to dryness and diluted with saturated brine. with chloroform. The organic layer was dried to give 144 mg of a brown tea which was purified by silica gel flash chromatography to give 31 mg of the title compound as a brown solid.

1 H NMR (CDCl 3) δ 1.1 - 2.0 (m, 9H), 2.8 - 3.0 (m, 30 (s, 2H), 6.76 (dd, 1H, 6.9 (s) , 1H), 6.96 (s, 1: ***: 7.3 (m, 6H) ppm.

··· 32

Example 25 1- (1-Ethyl-2-methyl-1H-benzimidazol-5 - [(1-phenylmethyl) -4-piperidinyl] -2-] one A mixture of 0.1 g (0.5 n 1-Ethyl-Styl-benzimidazol-5-ylmethyl-ketone and 0.1 mmol) 4-formyl-N-benzylpiperidine in 10 mL hydrofuran (THF) was cooled to -78 ° C under nitrogen. To this mixture was added dropwise 10 (0.5 mmol) lithium bis (trimethylsilyl) amide 1 in THF. The reaction mixture was stirred for -78 hours then warmed to room temperature] To the reaction mixture was added 10 mL of water and pH s <to 2.01 with hydrochloric acid (HCl). Mixture with 15 mL of ethyl acetate. The pH of the aqueous layer is then ≤ 3.0, 4.0, 5.0, 6.5 and

NaOH, extracting each time with 15 ml <acetate. The ethyl acetate extracts of i at 5.0 and 6.5 were combined, dried over sulfur sulfate (Na 2 SO 4) and evaporated to give 50 mg (26%) of the title compound as an oil. • V. Thin layer chromatography (TLC) (10: 1 CHCl3: CH3OH).

Rf 0.58.

; 1 H NMR (CDCl 3) δ 8.22 (s, 1H), 7.88 (d, 1H), 7.30; δ 6.90 (m, 5H), 4.14 (q, 2H), 3.50 (s, 2H), 3.05 2.85 (m, 2H), 2.61 (s, 3H), 1.4-2.1 (m, 5 · * ·· * (t, 3H) ).

Example 26 1- (1-Ethyl-2-methyl-1H-benzimidazole-5-30 [1- (phenylmethyl) -4-piperidinyl] -propyl chloride 33 and the ethanol solvent was evaporated. of 1: 1 ethyl acetate and water was adjusted to 8.5 with 1N sodium hydroxide

The ethyl acetate layer was dried (Na 2 SO 4) and cooled to give 0.1 g (72%) of the title compounds as an oil.

TLC (10: 1 CHCl 3: CH 3 OH), R f = 0.64.

1 H NMR (CDCl 3) δ 8.26 (s, 1H), 7.92 (d, 1H), 7.28 4.18 (q, 2H), 3.48 (s, 2H), 3.05 ( m, 2H), 2.85 δ 2.54 (s, 3H), 1.4-2.0 (m, 9H), 1.30 (t, 3H).

The oil was dissolved in ethyl acetate and a solution of HCl dissolved in was added dropwise to the starch. The resulting precipitate was filtered and filtered with hexane to give 0.105 g of the title compound as a hygroscopic white solid.

Mp = 165-167 ° C.

Mass Spectrum: 389.2 (p), 298.0 (p-91), 172.0 (p-2J (p-298, Base Peak)).

EXAMPLE 27 1- (2-Methyl-6-benzothiazolyl) -3- [1- (phenyl) -4-piperidinyl] -2-propen-1-one. A mixture of 0.191 g (0.001 mol) of 2-I * 6-benzothiazolylmethyl ketone (prepared by Si * <SS Sawhney, J. Singh, and OP Bansal) is es *** J 25 in J. Ind. Chem. Soc. , 12, 561 (1975)) * * / (0.001 mol) 4-formyl-N-benzylpiperidine •• TH in THF, cooled to -78 ° C under nitrogen atmosphere

* · *: To this solution was added dropwise 0.73 mL (0 C)

lithium diisopropylamide (1.5 molar) in 30 THF. The reaction mixture was stirred at -78 ° C for 1: *** then warmed to 0 ° C. The reaction was blocked with 34 CH 2 Cl 2: CH 3 OH (98: 2). The appropriate fractions combined to afford 0.122 g (32%) of the title compound as a solid. TLC (10: 1 CH 2 Cl 2: CH 3 OH) R f = 1 H NMR (CDCl 3) δ 8.42 (s, 1H), 7.9 (m, 2H), 7.5 (m, 5H), 6.9-7 , 1 (m, 2H), 3.52 (s, 2H), 2.95 2.8 (S, 3H), 1.4-2.5 (m, 7H).

Mass Spectrum: 376.1600. Calculated for C23h 2.6 ppm.

EXAMPLE 28 1- (2-Methyl-6-benzothiazolyl) -3- [1- (methyl) -4-piperidinyl] -1-propanone hydrolyzate. 0.120 g (0.319 mmol) of the free base of the compound of Example 27 was dissolved in 50 ml <50 mg of Pt 2 O was added and the mixture was hydrogenated at 15 cm 2 (50 psi) for 1 hour. The well was filtered and the ethanol was evaporated, giving 0.112 g (100%) of the title compound (free base as a solid) * TLC (10: 1 CH 2 Cl 2: CH 3 OH) R f = 0.5.

20 NMR (CDCl 3) δ 8.45 (s, 1H); 8.02 (dd, 2H), 7.25 3.5 (S, 2H), 3.02 (m, 2H), 2.85 (m, 2H), 2.83 (s, .V - 2 , 0 (m, 9H).

• · t

Mass Spectrum: 378 (p), 287 (p-91), 172 (p-206), 9: •. ^ basic peak).

This residue was dissolved in 15 ml of ethyl weapon * to which was added HCl dissolved in ethyl acetate ···· The precipitate formed was filtered and dried at 1 ··· V · to give 92 mg (70%) of the title compound.

Mp = 110 ° to 112 ° C.

: 30 Example 29: ***: N-Acetyl-4-aminoacetophenone? • 18 hours. A white solid * precipitated from the solution and was collected by filtration. The solid was washed with air and dried to give 3.32 N-acetyl-4-aminoacetophenone.

TLC (1: 1 CHCl3: EtOAc) Rf * 0.61.

1 H NMR (CDCl 3) δ 8.58 (br s, 1H), 7.90 (d, 2 (d, 2H), 2.56 (s, 3H), 2.19 (s, 3H).

Example 30 N-Benzoyl-4-aminoacetophenone A mixture of 5.0 g (0.37 mol) of 4-amd phenone, 4.7 ml (0.04 mol) of benzoyl chloride and (0.04 mol) of triethylamine was dissolved. 50 ml of nichloride (CH 2 Cl 2) and stirred at room temperature for 18 hours. The precipitate formed was filtered and washed with water. The residue was dissolved in chloroform (CHCl 3) with Na 2 SO 4. Evaporation of CHCl3 gave 4.2 N-benzoyl-4-aminoacetophenone.

Mp = 206 ° to 208 ° C.

1 H NMR (CDCl 3 + DMSO) δ 9.58 (br s, 1H), 7.80 (m, <20 (m, 3H), 2.44 (s, 3H).

Example 31 • V. N-acetyl-3-nitro-4-aminoacetophenone in 10 mL of chilled smoke 1 *; of pola was added portionwise to 1.0 g (5.6 mmol) of N-asc

***; 25 aminoacetophenone. The temperature was maintained at 5 ° C

The benzene ring was prevented from over-nitration ···· The solution was stirred for 15 minutes at 0 ° C and carefully poured onto ice. The yellow precipitate was collected by filtration to give 30 (34%) of the title compound.

TLC (2: 1 CHCl 3: EtOAc) R f = 0.78.

36

Example 32 N-Benzoyl-3-nitro-4-aminoacetophenone To 10 ml of a smoke-cooled polar cooled to -5 ° C was added portionwise 2.5 g (0.01 mol) of N-ber 5 4-aminoacetophenone. The temperature was maintained at 0 ° C. The reaction mixture was stirred for 10 minutes and the solution was poured onto ice. A solid precipitate formed which was collected by filtration, the material dissolved in chloroform and chromatographed on silica gel with CHCl 3 as eluent. The appropriate ones were combined and evaporated to give] (35%) of the title compound as a yellow solid air 1 H NMR (CDCl 3) δ 9.12 (d, 1H); 8.84 (s, 1H), 8.25 7.96 (d, 2H), 7.6 (m, 3H), 2.66 (s, 3H).

Example 33 3-E1- (1-Phenylmethyl) -4-piperidinyl] -1H-4-acetamidophenyl) -2-propen-1-one A solution of 2.6 g (11.7 mmol) of N-? 3-nitro-4-aminoacetophenone in 25 mL of THF, cooled to -60 ° C under nitrogen. To the solution] 4.7 ml (11.7 mmol) of N-butyllithium (2.5 molar · · · ·)) while maintaining the temperature at -60 ° C. The reaction mixture was stirred for 15 minutes containing 4-formyl-N-benzylpiperidine: · in 25 mL of THF was added dropwise keeping the reaction temperature below -55 ° C. The reaction mixture was stirred for 1 hour and then warmed to ··· ·. · ·. The reaction was quenched with warm water (10 mL) and extracted with ethyl acetate; The acetate extracts were combined, dried (N;

. * · *. evaporated to give a dark oil. T

37 * 1 H NMR (CDCl 3) δ 8.90 (d, 1H), 8.76 (s, 1H), 8.14 8.30 (m, 5H), 3.53 (s, 2H), 2.94 (m, 2H), 2.32 1.5-2.15 (m, 5H).

Example 34 3- [1- (Phenylmethyl) -4-piperidinyl] -1- (4-benzoylamidophenyl) -2-propen-1-one

A solution of 0.80 g (2.90 mmol) of esd 32 in the title compound in 30 mL of anhydrous TI was placed at -70 ° C under a nitrogen atmosphere. 1.2 ml (2.9 mmol) of N-butyld (2.5 molar solution in hexanes) was added dropwise giving n dark solution. The solution was stirred at -70 ° C for 10 md To this mixture was added dropwise a solution of 0.6 g (2.9 mmol) of 4-formyl-N-benzylpip in 15 mL of THF. The reaction mixture was slowly warmed

and stirred for 18 hours. The reaction was quenched with 25 mL of water and extracted with ethyl acetate. The ethyl acetate solutions were dried (Na evaporated. The residue was chromatographed on pogel and CHCl3: EtOAc (1: 1) as eluent. The fractions were combined to give 0.45 g (3 * of porcine compound as an amorphous solid).

? CHCl3: CH3OH), Rf = 0.67.

1 H NMR (CDCl 3) δ 9.14 (d, 1H), 8.82 (s, 1H), 8.22 δ 7.98 (d, 2H), 7.55 (m, 3H), 7.32 (m, 5H), 7.10 6.85 (m, 1H), 3.54 (s, 1H), 2.95 (m, 2H), 1, ···· (m, 7H).

• ··· Example 35 1- (3-Amino-4-acetamidophenyl) -3 - [(1-phenyl] tert-butyl) -4-piperidinyl] -1-propanone

A solution of 0.9 g (2.2 mmol) in ethyl acetate was added to give 0.9 g (100%) of the title compound as an oil.

1 H NMR (CDCl 3) δ 7.6 (s, 1H), 7.2-7.5 (m, 7H), 2H), 2.85 (m, 4H), 2.21 (s, 3H), 1 , 2-2.0 (m, 91) Mass spectrum: 379.2 (p), 202.3 (p-176.9), 172.3 (j 91.0 (p-288.3, base peak).

Example 36 1- (2-Methyl-1H-benzimidazol-5-yl) -3-ylmethyl) -4-piperidinyl] -1-propanol 10 chloride

A solution of 0.6 g (1.6 mmol) of the free base of the title compound in 10 ml of acid was heated in a steam bath (80 ° to 90 ° for 0 hours). The acetic acid was evaporated and the residue was taken up in 25 ml of ethyl acetate. 2 and the pH was adjusted to 3.0 The ethyl acetate was decanted from the aqueous layer and the aqueous layer was adjusted to pH 5.0, 6.0 and 9.0 by extraction with ethyl acetate The ethyl acetate extract obtained at pH 9.0 was dried (Na 2 SO 4) and evaporated to give 0.4 g (69%) of the title compound (free base as base).

1 H NMR (CDCl 3) δ 8.08 (s, 1H), 7.80 (s, 1H), 7.47. 7.25 (m, 6H), 3.47 (s, 2H), 2.8-3.0 (m, 4H), λ max: 25 3H), 1.90 (t, 2H), 1.64 (m, 4H), 1.25 (m, 3H).

TLC (10: 1: 0.1 CHCl 3: CH 3 OH: NH 4 OH), Rf (free base) ··· ···· The amorphous solid was dissolved in ethyl acetate ···

To the solution was added hydrogen chloride (HCl)

solution alone. The resulting precipitate was filtered and filtered to give 0.26 g (62%) of the title compound as a *** solid.

39

Example 37 X- (3-Amino-4-benzoyl-idophenyl) -3-ylmethyl) -4-piperidinyl] -1-propanone

To a solution of 0.45 g (1.0 mmol) of the title compound obtained in 5 ml 34 in 50 ml of etanc was added 25 mg of PtO 2 and the mixture was hydrogenated at 3.5 kg / ci for one hour. After removal of the catalyst by filtration, the title compound was evaporated to give the title compound as an amorphous solid 10 * NMR (CDCl 3)? 8.15 (s, 1H), 7.90 (d, 2H), 7.2 -10H), 3, 88 (br, s, 2H), 3.50 (s, 2H), 2.90 (m, 41 2.0 (m, 9H)).

This material was used in Example 38 without further purification.

Example 38 1- (2-Phenyl-1H-benzimidazol-5-yl) -3-methylmethyl) -4-piperidinyl] -1-propanone chloride

The title compound of Example 37 was dissolved in 20:50 acetic acid and heated 71 for 3 hours. The reaction mixture was cooled to room temperature and diluted with water. The pH of the mixture was adjusted to 9.5 and the mixture was extracted with ethyl acetate. E1 * ·. . the acetate extracts were dried (Na 2 SO 4) and evaporated; At 25 runs, 0.19 g (45%) of the free compound of the title compound was obtained.

TLC (10: 1: 0.1 CHCl 3: CH 3 OH: NH 4 OH), R f = 0.40.

1 H: 1 H NMR (CDCl 3) δ 8.14 (d, 2H), 7.86 (d, 1H), 7 (m, UH), 3.58 (s, 2H), 2.92 (m, 4H), 1,2-2,1: βß [: 30 The residue was dissolved in ethyl acetate and to the solution was added dropwise ethereal HCl solution> mm 40

Example 39 1- (2-Methyl-6-benzthiazolyl) -3- (4-piperidyl) -1-propanone

A mixture of 0.90 g (2.38 mmol) of 1- (5'-6-benzthiazolyl) -3- [1- (phenylmethyl) -4-pynyl] -1-propanone (Example 27) and 0.33 mL (2 1-chloroethyl chloroformate, heated under distillation under 10 mL of 1,2-dichloroethane for 1 hour. The resulting brown solution was cooled to 10 and diluted with 15 mL of water, extracted twice with 20 mL of ethyl acetate , dried (M evaporated to give 1.0 g (100%) of 1- (2-6-benzothiazolyl) -3 - [(1-chloroethylformyl) ridinyl] -1-propanone as an oil).

TLC (10: 1 CH 2 Cl 2: CH 3 OH) R f = 0.86.

1 H NMR (CDCl 3) δ 8.4 (s, 1H), 7.9 (m, 2H), 6.55 2.65-3.2 (m, 4H), 2.77 (s, 3H), 1.83 (d, 3H), 1, (m, 9H).

13 C NMR (CDCl 3, ppm) 198.1 171.3 155, 135.8, 133.4, 125.9, 122.1, 122.0, 83.3, 44.2 (2 35.3, 32 , 0, 30.4 (2), 24.4, 20.3.

A solution of 0.9 g (2.28 mmol) of edi * * oil in methanol (5 mL) was heated | I 25 for 1 hour under distillation conditions. After cooling, a yellow precipitate formed. This precipitate was dissolved in 4 m · and extracted with ether. PH of HCl solution Se · m * V: to 9 with sodium carbonate (Na 2 CO 3) and extracted acetate. The ethyl acetate extracts were dried; 30 and evaporated to give 0.250 g (38%) of: ***: amorphous yellow solid • 413 NMR (CDCl3, parts per million) 198.1, 156.3, 136 132.0, 125.9, 122 , 3, 122.1, 46.4 (2), 35.8, 35, 31.4 (2), 20.5.

Example 40 1- (2-Methyl-6-benzothiazolyl) -3- [1- (2- 4-thiazolyl) methyl] -4-piperidinyl] nonone hydrochloride

A mixture of 250 mg (0.87 mmol) of each of the 39 title compounds, 0.160 mg (0.87 mmol) of 2-10 4-chloromethylthiazole and 0.36 mL (2.60 mmol) of liamine was heated to reflux in 50 mL of methylene chloride 12 hours. Reaktioseo; was brought to room temperature and diluted with 1 water. The mixture was extracted with ethyl acetate and the ethyl extracts were combined, dried (Na 2 SO 4) and cooled to give 0.27 g of a yellow gum. 1 was chromatographed using 10 g of silica gel in CHCl3: CH3OH (98: 2). The appropriate fractions were collected and evaporated to give 100 mg (2 of 20 pigs as yellow amorphous solid c TLC (10: 1 CH 2 Cl 2: CH 3 OH 3, R f * 0.21).

1 H NMR (CDCl 3) δ 8.50 (s, 1H), 7.9 (m, 2H), 6.87 * · 3.62 (s, 2H), 3.0 (m, 4H), 2, 87 (s, 3H), 2.69 (s,; e. # (T, 2H), 1.7 (m, 4H), 1.35 (m, 3H).

Mass spectrum: 399.2 (p), 287.2 (p-112, base peak (p-176.1), 193.1 (p-206.1), 176.0 (p-223), 112, 0 71.0 (p-328).

This material was dissolved in ethyl acetate and ethereal HCl gas was added. My form 30 was filtered and recrystallized from CH 2 Cl 2 to give 92 mg of the title compound.

Example 41 1- (5-Amino-indol-2-yl) -3- [1- (phenyl-piperidinyl] -1-propanone A solution of 1- (1-phenylsulfonyl-5-indol-2-yl) -3 - (N-Phenylmethylpiperidine-4 · propanone (160 mg, 0.32 mmol) in a mixture of methanol and 2 mL of 2N NaOH was refluxed for 2 hours. The mixture was evaporated to dryness and diluted with saturated brine; 10 mL of organic layer. dried was dried to give 144 mg of a brown solid which was purified by silica gel chromatography to give 31 mg of the title as a brown solid.

15 NMR (CDCl 3) δ 1.1 - 2.0 (m, 9H), 2.8 - 3.0 (m, (S, 2H), 6.76 (dd, 1H), 6.9 (s, 1H), 6.96 (s, 11 7.3 (m, 6H) ppm.

Example 42 (5-N-Acetylamino-indol-2-yl) -3- [1- (trans) -4-piperidinyl] -1-propanone

A solution of 1- (5-aminoindol-2-yl [1- (phenylmethyl) -4-piperidinyl] -1-propanone, * 0.05 mmol) in 0.5 ml of methylene chloride, go * *. with a solution of triethylamine * "in 0.06 mmol) in 0.5 ml of methylene chloride, and a solution of acetyl chloride (4.7 mg, 0, * * · ···· 0.5 ml of methylene chloride, room temperature was stirred at room temperature for 4 hours, quenched with water and extracted with methylene chloride (30 ml) .The organic layer was dried and evaporated to give the title compound (11 ml).

Claims (5)

A process for the preparation of pharmaceutically acceptable salts of the therapeutically useful salts of the therapeutically useful heteroarylamine compounds of formula (I) wherein, instead of ring A, the side chain containing the group may alternatively be on the carbon atom marked with an asterisk; R 1 is phenyl, phenyl (C 1-6 alkyl, cinnamethyl, heteroarylmethyl wherein the heteroaryl portion of said heteroaryl is selected from the group consisting of • • • β · β Solo, thiazolo, thieno, pyrido and isoxazolo, and • · · ' ** * said phenyl and said heteroaryl moiety may be substituted at one or two substituents independently selected from the group consisting of (C 1 -C 6 alkyl, (C 1 -C 4) alkoxy and halo); : R 2 and R 3 are independently selected from the group consisting of m-hydrogen, {C 1-4 alkoxy, (C 1-4) alkyl optionally substituted with one to three fluorine atoms, the benzyloxy Y is oxygen, sulfur or NR 6; R 6 is hydrogen , (C 1 -C 4 alkyl, CO (C 1 -C 6) alkyl tolyl) wherein the phenyl portion of said SO 6 phenyl may be optionally substituted with 1 to 5 substituents independently selected from C 1 -C 4 alkyl; n is an integer from 1 to 4; is independently 1 or 2; and Z is oxygen or sulfur; a group already having 10 1 must be bonded to one and only one CHq group where q is 1; characterized in that: a) a compound of formula IA __________ wherein, instead of ring A, a side chain is: X; ψ * i * 1 -CH-, alternatively may be a bonded carbon; denoted by an asterisk in ring B, and R 2 and F ··· · 25 alternatively bonded to ring B, and ·; · R 1, R 2, R 3, x, y, q and n are as defined above, s! ··· with an oxidizing agent and reacting the compound thus formed to react r. with a compound capable of forming a compound of the formula wherein R1, R2, R3, x, y, q and n are as defined above] b) a compound of the formula IB r * 1 · 0 c-ch = ch- <chb n - '\ V - 5 where n is 2, 3 or 4 and the (CHq) n group always contains a} carbon-carbon double bond and R1, R2, R3 , x, yj <such as defined above, are reacted with rc hydrogen in the presence of a catalyst; or ίο c) a compound of the formula IC H · · k · «k · f *: ·: 1-C *”: wherein R 1 and R 2 are as defined above, is reacted with a compound of * ί * '; of the formula R 6 L, if * *; · 15 as defined above and h is a leaving group; or IMI d) reacting a compound of formula XV wherein R1, R2, R3, x, y, z, q and m are above with a compound having k <wherein L is a leaving group, in the presence of a base . 2. A process according to claim 1, characterized in that R @ 1> c ^ T; ^ xj '-' c '_ <CH * x o v "or wherein X is CH, CCH3 or N; Y is NH, NCH3, NCH2CH3, R 2 and R 3 are independently selected from (C 1 -C 6 alkyl, chlorine, fluorine, methoxy O ". 1 -NHCCH 3; and R is benzyl, methoxybenzyl,. [. * · Benzyl or a group of the formula •« • * «· * • · · K 3. H · - 3. A process according to claim 2, wherein the compound is CH, CCH3 or N; Y is NH, NCH 3, sulfur or oxygen; R is independently selected from the group consisting of alkyl, chloro, fluoro, methoxy, amino and O-NHCch 3, and R 1 is benzyl. 4. A process according to claim 3, characterized in that the compound 10 and R 3 are independently selected from the group consisting of (C 1 -C 4) alkyl, chlorine, amino and O-NHCCH 3. 5. A process according to claim 1, characterized in that the compound v is prepared from the group consisting of: 1- (2-methyl-1H-benzimidazol-5-yl) -3- [1- (phenyl) -4-piperidinyl ] -1-propanone hydrochloride; 1- (2-phenyl-1H-benzoimidazol-5-yl) -3- [1- (phenyl) -20i] -4-piperidinyl] -1-propanone hydrochloride; * * ** '· [1- (1-Ethyl-2-methyl-1H-benzimidazol-5-yl) -3- [* * ylmethyl) -4-piperidinyl] -1-propanone hydrochloride: 1- (2 -methyl-6-benzothiazolyl) -3- [1- (phenylmethyl 4-piperidinyl] -1-propanone hydrochloride; 1- (2-methyl-6-benzothiazolyl) -3- [1 - ((2-methyl- solyl) methyl) -4-piperidinyl] -1-propanone; * 1- (5-methylbenzo [b] thien-2-yl) -3- [1- (phenylmethyl) -4,4-piperidinyl] - 1-propanone; · · (6-methyl-benzo [b] thien-2-yl) -3- [1- (phenylmethyl) -1- (benzofuran-2-yl) -3- [1- (phenylmethyl) - 4-Piperyl] -1-propanone; 1- (1-phenylsulfonyl-6-methylindol-2-yl) -3- [1-methylmethyl) -4-piperidinyl] -1-propanone; 6-methylindol-2-yl) -3- [1- (phenylmethyl) -4-dinyl] -1-propanone; 1- (1-phenylsulfonyl-5-aminoindol-2-yl) -3- [ 1- (limethyl) -4-piperidinyl] -1-propanone; 1- (5-aminoindol-2-yl) -3- [1- (phenylmethyl) -4-piperidinyl] -1-propanone; and 1- {5-acetylamino-indol-2-yl) -3- [1- (phenyl) methyl piperidinyl] -1-propanone. • 1 • «· • ·« • «• 1 • ♦ * · ·« «· # ··» • 1 ♦ t ik »« • · · • 1 · • · · • 4 M »1« 11